A Phase II/III Randomized Study of Brigimadlin (BI 907828) Versus Doxorubicin in First-Line Treatment of Advanced Dedifferentiated Liposarcoma
- Trial ID
- 2024-511361-11-00
- Protocol
- 1403-0008
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate whether **brigimadlin** is superior to **doxorubicin** as first-line systemic therapy for advanced or metastatic dedifferentiated liposarcoma (DDLPS). This is clinically relevant as it aims to improve treatment outcomes for patients with this aggressive form of cancer, potentially offering a more effective therapeutic option.
Secondary objectives include:
- Phase II part: Select an optimal dose of brigimadlin.
- Phase II part: Evaluate whether the expected benefits of brigimadlin as first-line systemic therapy for advanced or metastatic DDLPS outweigh any risks.
- Phase III part: Evaluate whether brigimadlin as first-line systemic therapy for advanced or metastatic DDLPS improves the objective response rate, duration of responses, overall survival, disease control rate, tolerability, and has a favorable impact on quality of life, compared to doxorubicin.
- Safety of brigimadlin will be investigated in both parts of the trial.
Participants
The clinical trial involves a total of **190 participants** diagnosed with **advanced dedifferentiated liposarcoma**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including a histologically confirmed diagnosis of locally advanced or metastatic, unresectable, progressive, or recurrent dedifferentiated liposarcoma. The trial population is characterized by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating that participants are fully active or restricted in physically strenuous activity but ambulatory. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, and participants are required to provide informed consent and comply with contraceptive measures if applicable. The selection process ensures that participants have at least one measurable target lesion according to RECIST version 1.1 criteria.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, multi-center study to evaluate the efficacy of brigimadlin (BI 907828) compared to doxorubicin in patients with advanced dedifferentiated liposarcoma. The trial is structured in two phases, Phase II and Phase III, with the primary objective being to assess whether brigimadlin is superior to doxorubicin as a first-line systemic therapy. The trial is expected to conclude by May 27, 2026, with recruitment having commenced on March 31, 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological diagnosis, and performance status. Following randomization, participants will receive either brigimadlin or doxorubicin, with the treatment regimen tailored to the specific drug. Brigimadlin is administered orally in the form of a **film-coated tablet**, while doxorubicin is given as an **intravenous infusion**. The maximum treatment period for brigimadlin is 21 days, whereas doxorubicin can be administered for up to 126 days.
Study visits will include regular follow-up assessments to monitor progression-free survival (PFS), objective response (OR), and overall survival (OS), among other secondary endpoints. These assessments will be conducted through central independent review, ensuring unbiased evaluation of treatment efficacy. Participants will also be required to provide blood samples for pharmacokinetic and pharmacodynamic analyses, as well as tumor mutation analysis.
The end-of-study visit will mark the conclusion of a participant's involvement, during which final assessments will be conducted to evaluate the overall health status and any treatment-emergent adverse events. Participant involvement is expected to last until the end of the treatment period or until disease progression, unacceptable toxicity, or withdrawal of consent occurs. Conditions that may lead to early termination from the study include significant adverse events or non-compliance with study protocols.
Treatment
The clinical trial involves the administration of **BI 907828**, an experimental medication formulated as a **film-coated tablet**. The active substance in BI 907828 is a chemical compound known as (3S,3'S,3A'S,10A'S)-6-chloro-3'-(3-chloro-2-fluorophenyl)-1'-(cyclopropylmethyl)-6'-methyl-2-oxo-1,2,3',3A',10',10A'-hexahydro-1'H-spiro[indole-3,2'-pyrrolo[2',3':4,5]pyrrolo[1,2-b]indazole]-7'-carboxylic acid. The medication is administered orally with a maximum daily dose of 30 mg, 45 mg, or 20 mg, depending on the specific formulation used in the trial. The total maximum dose for each formulation is 900 mg, 1350 mg, or 600 mg, respectively, over a treatment period of 21 days. The medication is of chemical origin and is not a pediatric formulation. Participant compliance is monitored through regular assessments and adherence checks.
The comparator treatment in this study is **Doxorubicin-Ebewe**, a standard-of-care therapy for advanced dedifferentiated liposarcoma. This medication is provided as a **solution for infusion** with the active substance being **doxorubicin hydrochloride**. Doxorubicin-Ebewe is administered via **intravenous infusion** with a maximum daily dose of 75 mg/m² and a total maximum dose of 450 mg/m² over a treatment period of 126 days. This medication is also of chemical origin and is not formulated for pediatric use. Compliance with the dosing schedule is ensured through infusion records and monitoring by clinical staff.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, which will be evaluated based on central independent review. This assessment will occur at the interim futility analysis, approximately coinciding with the end of Phase II, and the primary PFS analysis will be conducted during the Phase III part of the trial.
Secondary endpoints include **Objective Response (OR)**, defined as a best overall response of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.1, based on blinded central independent review. The duration of objective response (DOR) will be measured from the first documented confirmed OR until disease progression or death. **Overall Survival (OS)** will be assessed at the end of the Phase III part, defined as the time from randomization until death from any cause. **Disease Control (DC)** is defined as a best overall response of CR, PR, or stable disease (SD) according to RECIST version 1.1.
Additionally, Health-Related Quality of Life (HRQoL) will be evaluated using specific questionnaires, with data analyzed from baseline to Week 6 and Week 18. The HRQoL endpoints are derived from scores calculated through selected EORTC QLQ-C30 domains, including physical functioning, pain, fatigue, and global health status/quality of life, as well as the EQ-5D5L. The occurrence of treatment-emergent adverse events (AEs) and those leading to study drug discontinuation will also be monitored.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Provision of signed and dated, written informed consent form ICF in accordance with ICH-GCP and local legislation prior to any trial-specific procedures, sampling, or analyses.
- Male or female patients ≥18 years old at the time of signature of the ICF. Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use 2 medically acceptable methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly beginning at screening, during trial participation, and until 6 months and 12 days after last dose. A list of contraception methods meeting these criteria is provided in the patient information.
- Histologically proven locally advanced or metastatic, unresectable (surgery morbidity would outweigh potential benefits), progressive or recurrent DDLPS. Locally performed histopathological diagnosis will be accepted for entry into this trial but will be confirmed by independent pathological review while the patients receive treatment in this trial.
- Written pathology report indicating the diagnosis of DDLPS with positive MDM2 immunohistochemistry or MDM2 amplification as demonstrated by fluorescence in situ hybridization or NGS must be available.
- Formalin fixed paraffin embedded tumor blocks or slides must be available for retrospective histopathological central review.
- Presence of at least one measurable target lesion according to RECIST version 1.1. In patients who only have one target lesion, the baseline imaging must be performed at least 2 weeks after any biopsy of the target lesion.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
- Patient must be willing to donate blood samples for the pharmacokinetics, pharmacodynamics, and tumor mutation analysis.
- Further inclusion criteria apply.
Exclusion Criteria
- Known mutation in the TP53 gene (screening for TP53 status is not required).
- Major surgery (major according to the investigator’s assessment) performed within 4 weeks prior to randomization or planned within 6 months after screening.
- Prior systemic therapy for liposarcoma in any setting (including adjuvant, neoadjuvant, maintenance, palliative).
- Previous or concomitant malignancies other than DDLPS or WDLPS, treated within the previous 5 years, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ, or other malignancy that is considered cured by local treatment.
- Previous treatment with anthracyclines in any setting (systemic treatment with other anticancer agents is allowed if completed at least 5 years prior to study entry with the exception of hormone therapy).
- Patients who must or intend to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial.
- Currently enrolled in another investigational device or drug trial, or less than 30 days since ending another investigational device or drug trial(s) or receiving other investigational treatment(s).
- Patients not expected to comply with the protocol requirements or not expected to complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition that, in the investigator’s opinion, makes the patient an unreliable trial participant).
- Further exclusion criteria apply.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 31 Mar 2022 | 20 |
 Czechia | Not Recruiting | 31 Mar 2022 | 7 |
 Finland | Not Recruiting | 31 Mar 2022 | 3 |
 France | Not Recruiting | 31 Mar 2022 | 44 |
 Germany | Not Recruiting | 31 Mar 2022 | 21 |
 Greece | Not Recruiting | 31 Mar 2022 | 8 |
 Italy | Not Recruiting | 31 Mar 2022 | 67 |
 The Netherlands | Not Recruiting | 31 Mar 2022 | — |
 Norway | Not Recruiting | 31 Mar 2022 | 2 |
 Portugal | Not Recruiting | 31 Mar 2022 | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
BI 907828 | Test | FILM-COATED TABLET | ORAL | 30 | 21 | PRD10565907 |
BI 907828 | Test | FILM-COATED TABLET | ORAL | 20 | 21 | PRD10565901 |
Doxorubicin-Ebewe, 2 mg/ml, koncentrat do sporządzania roztworu do infuzji | Comparator | KONCENTRAT DO SPORZĄDZANIA ROZTWORU DO INFUZJI | INTRAVENOUS INFUSION | 75 | 126 | PRD766672 |
BI 907828 | Test | FILM-COATED TABLET | ORAL | 45 | 21 | PRD10565911 |